P688: ASC2ESCALATE: A US PHASE 2, OPEN-LABEL, SINGLE-ARM, DOSE-ESCALATION STUDY OF ASCIMINIB MONOTHERAPY IN 2ND-LINE (2L) TREATMENT OF PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP)
Authors: Ehab Atallah, Michael Mauro, Koji Sasaki, Moshe Yair Levy, Paul Koller, Islam Sadek, Daisy Yang, Julie Ruckel-Kumar, Mahmudul Khan, Jorge Cortes
Journal: HemaSphere (2023)

Background: ATP-competitive TKIs extend life expectancy in CML; yet up to 40% of newly diagnosed pts with CML-CP stop 1st-line (1L) therapy by 5 years mainly due to resistance or intolerance and switch to 2L therapy. There is also an unmet need to overcome high rates of resistance in 2L. Dose-escalation studies show that some pts with resistance can achieve responses with higher doses of their TKI. Asciminib is the 1st BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), allowing asciminib to have activity against most BCR::ABL1 mutations that impart resistance to ATP-competitive TKIs. Asciminib was 1st approved in the United States for pts with CML-CP after ≥2 TKIs at 80 mg once daily (QD) and 40 mg twice daily (BID) and CML-CP with the T315I mutation at 200 mg BID. In the phase 3 ASCEMBL study, asciminib 40 mg BID showed superior efficacy vs bosutinib 500 mg QD in pts with CML-CP after ≥2 prior TKIs at weeks 24 (major molecular response [MMR], 25.5% vs 13.2%) and 96 (MMR, 37.6% vs 15.8%) and favorable tolerability with >2 years’ follow-up. In a large phase 1 dose-finding trial, asciminib was safe across doses of 80 to 200 mg QD and 10 to 200 mg BID in pts with CML-CP/accelerated phase without and with the T315I mutation previously treated with ≥2 and ≥1 TKIs, respectively, with no maximum tolerated dose reached. We describe the phase 2 ASC2ESCALATE trial evaluating dose escalation of asciminib in 2L treatment of pts with CML-CP (NCT05384587). Aims: The primary objective of this study is to evaluate the efficacy and safety of asciminib monotherapy as a 2L treatment for patients with CML-CP who have experienced treatment failure or intolerance to 1 prior ATP-competitive TKI. Methods: This is a phase 2, open-label, multicenter, single-arm, dose-escalation study in the United States (Figure). Adults (aged ≥18 years) with CML-CP without the T315I mutation who received 1 prior ATP-competitive TKI and discontinued due to resistance (BCR::ABL1IS >10% with 6-12 months of 1L treatment or >1% with >12 months of 1L treatment) or intolerance (BCR::ABL1IS >0.1% with ≥6 months of treatment) and provide informed consent are eligible. All pts will start treatment with asciminib 80 mg QD. For pts not achieving BCR::ABL1IS ≤1% at 6 months, dose will be escalated to 200 mg QD. Patients who achieve this response will continue at 80 mg QD. In pts not achieving MMR at 12 months, either dose escalation from 80 to 200 mg QD or from 200 mg QD to 200 mg BID will occur or the pts will discontinue study treatment. Pts achieving MMR at 12 months will continue asciminib at their current dose. If patients have grade ≥3 or persistent grade 2 toxicity refractory to optimal management, no dose-escalation will occur. Pts who clinically benefit from asciminib per investigator assessment may receive post-trial access. Pts may discontinue any time due to unacceptable toxicity or progression or at investigator/pt discretion. Results: The primary endpoint is the proportion of pts achieving MMR at 12 months. Secondary endpoints include MMR rates by 3, 6, 18, and 24 months, MR4.5 (BCR::ABL1IS ≤0.0032%) at 24 months, and safety/tolerability measures. Summary/Conclusion: ASC2ESCALATE is the 1st clinical trial designed to assess asciminib in pts with CML-CP requiring 2L therapy and seeks to provide practical guidance for the use of asciminib in patients with CML-CP requiring a treatment switch due to intolerance of or resistance to 1L therapy. Recruitment for this study began August 2022 with an estimated enrollment of 92 pts with CML-CP across ≈40 sites. This study is sponsored by Novartis.Keywords: Dose escalation, Asciminib, Chronic myeloid leukemia